This proposed Physician Scientist Award will enable me to pursue further training and research directed toward understanding the contribution of pubertal changes on the expression of affective illness, and the potential use of biological markers in juvenile depression. The training will provide the background to develop research strategies using pharmacologic probes to assess sleep and hormone regulation related particularly to the cholinergic system in juvenile populations. The study of adolescent depressives should help clarify what sleep and neuroendocrine abnormalities are state and trait correlates of affective illness in this age group. The proposed training and research is divisible into Phase I and Phase II: During the first two years of the funding period, Phase I, I will be immersed in a basic science learning experience consisting of didactic instruction in neurochemistry, statistical training, and sleep physiology, along with supervised laboratory work. The focus of Phase I will be to attain a thorough understanding of radioimmunoassay (RIA) methods for drug and hormone measurement, experience in the application of pharmacologic probes and stress paradigms in animals, and an understanding of responsiveness of cholinergically regulated hormone systems across developmental periods in animals. Phase II, or the second three years of proposed work, will involve clinical studies using the probes studied preclinically in Phase I in populations of depressed and recovered adolescents, non- depressed adolescents with other psychiatric illnesses, siblings of depressed adolescents, and normal volunteer adolescents. The proposed research, in addition to facilitating my career development, should shed light on what neuroendocrine abnormalities are central to affective illness at all ages, versus those that are epiphenomena of aging, exposure to stressors or repeated episodes of illness; and whether changes in cholinergic responsiveness with age underlie these abnormalities. This training will enable me to independently develop other potential pharmacologic probes for application in future studies of juvenile psychiatric disorders.